The proposed research project is designed to characterize the molecular pathophysiology and clinical consequences of iron-induced cardiac disease using a coordinated series of studies of cardiac myocytes in culture, of the first animal model of the cardiomyopathy of iron overload, and of patients with thalassemia major. Iron-induced myocardial disease is the most frequent cause of death in thalassemia major and is a major life-limiting complication of other transfusion- dependent refractory anemias hereditary hemochromatosis and other forms of iron overload. We hypothesize that (i) the body iron burden is a principal determinant of the magnitude of cardiac iron deposition in patients with thalassemia major, (ii) the nonuniform pattern of iron deposition in the heart results in variability in iron concentrations within cardiac myocytes, and (iii) the increased intracellular iron selectively affects specific ion channels in cardiac myocytes, producing abnormalities in sodium and potassium currents that result in aberrant ventricular repolarization and contribute to arrhythmogenesis. The proposed research has three specific aims: (1) to determine the pathophysiologic mechanisms responsible for iron-induced abnormalities of Na+ and K+ currents in cultured neonatal rat cardiac myocytes and the effects of iron chelators, antiarrhythmic drugs and other agents; (2) to examine the effects of excess iron, iron chelators, antiarrhythmic drugs and other agents on cardiac electrophysiology and function in a gerbil model of iron overload both in the intact animal and in isolated heart preparations; and (3) to determine the relationship in patients with thalassemia major between body iron burden, as measured by non- invasive magnetic susceptometry, and abnormalities of cardiac rhythm and function, as assessed as assessed by the signal-averaged electrocardiogram, T wave alternans, dynamic measures of the QT interval and echocardiography. This research will result in new fundamental information about the molecular basis for the effects of iron on cardiac ion channels, will provide the first electrophysiolgical and functional studies in a new animal model of iron overload, and will develop new non-invasive means of identifying those patients at the highest risk for iron-induced cardiac disease to permit intensive iron chelation therapy and other preventive interventions.